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Introduction

CHAPTER I

Introduction

Natural, synthetic and semisynthetic heterocyclic compounds play an important role in

drug discovery and chemical biology. The heterocycles are mainly of the classes of

alkaloids, flavones, isoflavones, chromans, chromones, coumarins and chromenes.

Synthetic compounds of these classes show different biological activity. More than 50% of

the drugs used in the modern medicine are either derived from natural or synthetic

heterocyclic system. A brief account of the biologically active oxygen heterocycles which

are used as drugs or in various stages of development as drugs are reviewed here.

1) Bioactive coumarins, chromans, chromones and triterpenoids:

1.1) Bioactive coumarins:

Coumarin (2H-chromen-2-one or 2H-1-benzopyran-2-one) (1) and its derivatives are

ubiquitously distributed in nature and many of them exhibit diverse and useful biological

activities1, 2

. These compounds have numerous medicinal applications including antitumor,

anti-HIV therapy 3, 4

, central nervous system (CNS) stimulation 5, antibacterial

6, 7,

anti-inflammatory 8–10

and anti-coagulant properties 11

. In addition, hydroxycoumarins are

known to be powerful chain-breaking anti-oxidants which can prevent free radical injury

by scavenging reactive oxygen species 12, 13

. Some coumarin derivatives display cytostatic

properties, while others have cytotoxic activities 14

. For example coumarin and its active

metabolite 7-hydroxycoumarin (2) have demonstrated growth-inhibitory activity in human

cancer cell lines such as A549 (lung), ACHN (renal), H727 (lung), MCF-7 (breast), HL-60

(leukemia), anti-proliferative activity in prostate cancer, malignant melanoma and

metastatic renal cell carcinoma in clinical trials 15–18

. The recent discovery of coumarins

having weak estrogenic activity resulted in the use of such derivatives as therapeutic agents

in preventing the emergence of menopause-related diseases such as osteoporosis, increased

risk of cardiovascular disease and cognitive deficiencies 19

. Furthermore, the substituted

pyranobenzothiazinones exhibited estrogenic activity in MCF-7 breast carcinoma cells 20

.

Of particular interest in breast cancer chemotherapy is the finding that some coumarin

analogs and their active 7-hydroxycoumarin metabolites have sulfatase and aromatase

Introduction

inhibitory activities. Coumarin-based selective estrogen receptor modulators (SERMs) and

coumarin estrogen conjugates have also been described as potential anti-breast cancer

agents 21

. The anti-tumor activities of coumarin and its metabolite 7-hydroxycoumarin

were tested in several human tumor cell lines by Steffen et al. 22

and Cai et al 23

. Both

compounds inhibited cell proliferation of gastric carcinoma cell line (HSC-39), colon

carcinoma cell line (Caco-2), hepatoma-derived cell line (Hep-G2) and lymphoblastic cell

line (CCRF). The effect of warfarin (3) on tumor cell growth was studied 24

. Warfarin

inhibits metastasis of Mtln3 rat mammary carcinoma without affecting primary tumor

growth. Seven known coumarins showing significant cytotoxic activities on P388 cell lines

were isolated from the roots of Angelica gigas (Umbelliferae) 25

. The cytotoxicity of 22

natural and semi-synthetic simple coumarins was evaluated in human small cell lung

carcinoma cell line GLC4 and human colorectal cancer cell line COLO 320 using the MTT

assay 26

. Furthermore, a number of 4-hydroxycoumarin derivatives have been studied for

their HIV integrase inhibitory potency 27

. The main purpose was to simplify the large

structure of the compounds while maintaining their potency. It was found that the

minimum active pharmacophore consisted of coumarin dimer containing aryl substituent

on the central linker, methylene.

Figure-1.1: Some examples of bioactive coumarins.

Introduction

Recent reports suggest that coumarin derivatives can be explored as COX-2 inhibitors,

MAO-B inhibitors, CK-2 inhibitors and BACE-1 inhibitors.

Manojit Pal 28

et al reported recently a series of novel N-substituted 2-(coumarin-4-yloxy)-

propanamide derivatives as potential inhibitors of COX (Scheme-1).

Scheme 1: N-substituted 2-(coumarin-4-yloxy)propanamides as cyclooxygenase inhibitors:

Kraus 29

roup synthesized two series of new aryl-piperazine derivatives possessing either

naphthyl or coumarinyl moieties and determined their inhibitory activities on BACE-1

enzyme (Scheme-2). The structure-activity data for the two series of derivatives bring to

light the importance of substituents located at the N4-position of the piperazinyl ring.

Some new analogues bearing at this position a side chain with a hydroxy group were

highly potent BACE-1 inhibitors in both enzymatic and cell assays.

Scheme 2: Naphthyl and coumarinyl biarylpiperazine derivatives as highly potent human

β-Secretase inhibitors:

Introduction

Vina 30

reported a series of 3-substituted coumarin derivatives as inhibitors of MAO and

AChE. Introduction of an amide group between the 3-substituted aryl rings and the

coumarin afforded compounds which behave as dual inhibitors of MAO (mainly MAO-B)

and AChE in the micromolar range (Scheme-3).

Scheme 3: 3-Substituted coumarins as dual inhibitors of AChE and MAO:

1.2. Coumarin drugs:

Coumarins show quite diverse biological activities including anticoagulant, antiallergic,

vasodilatory, anthelmintic, diuretic, insecticidal and antibiotic properties 31-34

.

1.2.1. Anticoagulant compounds:

The anticoagulant properties of dicoumarol (11) [3,3-methylene-bis(4-hydroxy coumarin)]

isolated from spoiled sweet clover hay were discovered in 1941 . This discovery led to the

synthesis of a series of coumarin derivatives (12, 13) with anticoagulant properties.

Dicoumarol (11) which can be readily synthesized by condensing 4-hydroxycoumarin with

formaldehyde 35

has been identified as the cause of sweet clover disease in cattle 36

. This

compound has also been used in medicine to reduce blood-clotting in patients suffering

from cardiovascular disease. The anticoagulant properties of such 4-hydroxycoumarins are

due to their ability to inhibit the synthesis of the coagulant factor vitamin K in the liver.

The process of clotting involves polymerisation and cross linking of a soluble serum

protein prothrombin into a hard insoluble polypeptide known as fibrin 37

Introduction

Figure 1.2: Examples of anticoagulants

Warfarin (3) is perhaps the best known anticoagulant. It is widely used as a rodenticide

and for the treatment of various thromboembolic diseases 38-39

. Coumarin glycosides show

significant potential as oral antithrombotic agents. For example, iliparcil (14) a xyloside

has been reported to exhibit interesting antithrombotic activity limited, however by its

ready hydrolysis in vivo. In order to increase the bioavailability of iliparcil, the

enantiomeric analogues (+)-15 and (-)-16 were prepared, the laevorotatory enantiomer

being found to be the more active as an oral antithrombotic agent in rats 40.

Figure 1.3: Some examples of antithrombotic agents

1.2.2 Antibiotic and antibacterial coumarins:

Novobiocin (17) and chlorobiocin (18) are naturally occurring antibacterials which have

been isolated from certain Streptomyces species 41

. However their toxicity and poor

pharmacokinetic properties have prevented their use as antibiotics. Musicki et al 42-45

studied the structure-activity relationships of a series of coumarin bases as DNA gyrase

inhibitors. The results of their work led to stereoselective synthesis of 5-monoalkyl and

Introduction

5,5-dialkyl-substituted noviose derivatives from L-arabinose and the development of two

series of DNA gyrase inhibitors in which the coumarin moiety is replaced by

isothiochroman-2,2-dioxide and 1,2-benzooxathin-2,2-dioxide moieties.

Figure 1.4: Examples of antibiotic agents

Novobiocin and chlorobiocin are naturally occurring antibacterials which have been

isolated from certain Streptomyces species 45

. However their toxicity and poor

pharmacokinetic properties have prevented their use as antibiotics. Chatreaux et al 45

prepared analogues of the antibiotic novobiocin containing highly functionalized coumarin

structures and exhibiting improved pharmacological and pharmacokinetic properties. The

coumarin-based antibiotics possess a 3-amino-4-hydroxycoumarin moiety and a

substituted deoxysugar (noviose) which constitute a common core essential for biological

activity. Kinetic and structural studies have shown that the coumarin-based antibiotics are

competitive inhibitors of ATP binding to the gyrase B subunit while labelling studies have

established that the substituted coumarin moiety is biosynthesised from L-tyrosine and the

deoxysugar from D-glucose 46

.

1.2.3 Biologically active fluorescent and photostable coumarins:

3-Substituted 7-hydroxycoumarins have been shown to act as photostable laser dyes that

emit in the blue-green region of the visible spectrum. The emission range increases when

the 3-substituent is a heterocyclic moiety 47

and Abdallah et al 48

have reported the

synthesis 15 new 3-substituted 7-hydroxycoumarins [e.g. compounds 21(X = S, NH, O)]

Introduction

designed to extend the tunability range and maximise output. This work was based on the

assumption that the introduction of biologically active heterocycles at position-3 could lead

to physiologically active fluorescent compounds of biological interest 49-50

.

Figure 1.5: Fluorescent and photostable coumarins

1.2.4 Potential antipsychotic compounds:

A series of compounds containing a bulky lipophilic group such as cyclohexyl at position 4

(e.g. compound 22) were reported as potential antipsychotic compounds 51-53

Figure 1.6: Example of an antipsychotic compound

1.2.5 Anti-HIV compounds:

Figure 1.7: Examples of anti-HIV compounds

Introduction

Many natural products or their derivatives have anti-HIV activity or inhibit essential viral

enzymes 54-57

. Suksdorfin (23) which was isolated from the fruit of Lomatium suksdorfii

was found to be able to inhibit HIV. In an attempt to discover more potent and selective

anti-HIV compounds, Kuo-Hsiung Lee et al 58

investigated the synthesis and anti-HIV

activity of dihydroseselins (24).

1.3. Biologically active chromans:

Substituted chromans show a variety of biological action and several of these compounds

are used as drugs. Cromakalim (25) is an ATP sensitive potassium channel opener and is

used for the treatment of cardiac problems 59

. Centochroman (26) developed by CDRI is at

present used in India as an birth control pill (contraceptive agent) and is marketed as

“saheli”. It is one of the few non steroidal contraceptive agents used in birth control 60

.

7,8-Dihydroxy-3-amino-chroman-4-ol (27) and 6,7-dihydroxy-3-amino-chroman-4-ol (28)

have adrenergic receptor antagonist action. 7,4'-Dihydroxy isoflav-3-ene (phenoxodiol)

(29) is under clinical trials as an anti cancer drug 61

. Chromone alkaloids schymannificine

(30), N-methylschymannificine (31) are inhibitors of HSV-1 antigen production with low

toxicity. Rotenone (32) isolated from Derris elliptica, a chromanochroman is a natural

insecticide 62

.

Figure 1.8: Some examples of bioactive chromans

Introduction

Figure 1.9: Some examples of bioactive chromans

1.4) Bioactive chromones:

Disodium cromoglycate (33) is an anti allergic drug used to treat asthma 63

. Several

heterocycle substituted chromones are biologically active. 2 and 3-tetrazolyl chromones

(34), (35) show antiallergic activity 64

, 2-Morpholino-8-phenyl-chromone (36) is a

competitive inhibitor for the ATP binding site of P13-kinase. 2-(3-Pyridyl)-chromone (37)

shows bacteriostatic, tuberculostic, central nervous system depressant, antitumor and

insecticidal properities 65, 66

. 2-(2-(Furyl-2-vinyl)-3-nitrochromone (38) and 2-(2-furyl)-7-

hydroxy-chromone (39) protect plants from pathogens, fungi, bacteria and insects 67, 68

.

Figure 1.10: Some examples of bioactive chromones

Introduction

1.5) Bioactive triterpenes: Betulinic acid and its derivatives

Triterpenes represent a varied class of natural products. Thousands of structures have been

reported with hundreds of new derivatives described each year 69

. Among these are

included the pentacyclic lupane-type triterpenes which are represented by a diverse

assemblage of bioactive natural products. 3β-Hydroxy-lup-20(29)-en-28-oic acid

(betulinic acid) (40), a C-28 carboxylic acid derivative of the ubiquitous triterpene betulin

is a member of the class of lupane type triterpenes. However unlike betulin the oxidized

derivative betulinic acid possesses a number of intriguing pharmacological effects

including anti-inflammatory, anticancer and anti-HIV activities.

Betulinic acid (40) is found widely throughout the plant kingdom. Hundreds of published

reports have described the occurrence of betulinic acid across a multitude of taxonomically

diverse genera. One of the most widely reported sources of betulinic acid is the birch tree

(Betula spp., Betulaceae) where both betulinic acid and betulin can be obtained in

substantial quantities.71-73

Other known sources of betulinic acid include Ziziphus spp.

(Rhamnaceae),74-76

Syzygium spp. (Myrtaceae),77,78

Diospyros spp. (Ebenaceae)79-81

and

Paeonia spp. (Paeoniaceae).82-84

A multitude of extraction and isolation schemes have

been used for the procurement of betulinic acid and other related triterpenoids. Typically

dry plant material is extracted with CHCl3 (for aglycons),85

MeOH (for both aglycons and

glycosylated derivatives),85-87

or even H2O.88

The plant may be defatted with hexane prior

to extraction to remove non-polar materials.80,89

The resultant extracts can be dried and

further extracted with other solvents 86,87

or directly subjected to purification by

column chromatography 76,90–94

.

Derivatization of betulinic acid:

There exists a great deal of interest in probing the structural features responsible for the

pharmacological effects of betulinic acid and to further optimize its activity profile. As a

result numerous derivatization studies have been performed on betulinic acid leading to the

production of an array of betulinic acid analogs. Betulinic acid possesses three sites that

are highly amenable to derivatization including the C-3 hydroxyl, C-20 alkene, and C-28

carboxylic acid positions. Triterpenes, such as betulinic acid (BA), (40), 95

represent a

promising class of anti-HIV agents with novel mechanisms. From modified triterpenes,

Introduction

bevirimat [3-O-(3′,3′- dimethylsuccinyl)betulinic acid] (41) was found to exhibit

remarkable anti-HIV-1 activity against primary and drug resistant HIV-1 isolates 96-97

.

Figure 1.11: Some examples of bioactive triterpenes

2) OBJECTIVES AND SCOPE OF THE PRESENT STUDY:

Since many substituted coumarins have a diverse range of biological activities, the

present work is planned so as to synthesize new heterocycles pendent on the coumarin ring

at 4,6,7,8 positions and fused to coumarin ring at 7,8 positions by applying the various

synthetic strategies.

The results of the present study are discussed in 6 chapters.

1) Biological activity of oxygen heterocyclic systems and triterpenes are reviewed in

Chapter-I.

2) i) Chapter II (Section A) describes the regioselective synthesis of ethyl-3-[7-

benzyloxy]-4-methyl-2-oxo-2H-8-chromenyl]-5-aryl-4,5-dihydro-4-isoxazole

carboxylates via NCS mediated intermolecular 1,3-dipolar cycloaddition of

coumarin nitrile oxides.

ii) Chapter II (Section B) describes the synthesis of 8,9-substituted-3a,4-

dihydropyrano[2',3':5,6]chromeno[4,3-c]isoxazol-10(3H)-ones via CAN mediated

intramolecular 1,3 dipolar cycloaddition of O-allyl oximes.

Introduction

iii) Chapter II (Section C) describes the synthesis of 8,9-substituted-

pyrano[2',3':5,6]chromeno[4,3-c]isoxazol-10(4H)-ones via CAN mediated

intramolecular 1,3 dipolar cycloaddition of O-propargyl oximes.

3) Chapter III describes the synthesis of 4/6/7-[(3-aryl-1,2,4-oxadiazol-5-yl)methoxy]-

coumarins by using O-alkylated hydroxy coumarins and amide oximes.

4) Chapter IV describes the synthesis of O-alkyl hydroxamic acids, N-(benzyloxy)-2-

(4-H/Methyl-coumarin-4/6/7-yloxy)-acetamides by amide coupling of coumarin

4,6,7-yloxyacetic acids and O-(substituted benzyl)-hydroxylamines.

5) Chapter V describes the synthesis of C-28 modified 1,2,4-oxadiazole esters and

amides of betulinic acid via esterification and amide coupling strategies.

6) Chapter VI, Section A describes the biological screening of molecules in the

Eli Lilly-Open Innovation Drug Discovery Programme for endocrine,

cardiovascular, oncology, neuroscience and tuberculosis activity. Section B deals

with the evaluation of the antibacterial and antifungal activity of synthetic

coumarin derivatives and Section C describes cytotoxicity of semisynthetic

analogues of betulinic acid.

3) General methods of coumarin synthesis:

Many synthetic routes to the coumarins have been developed. These include use of the

Knoevenagel,Wittig, Perkin and Pechmann reactions etc.

3.1) Knoevenagel condensation:

Knoevenagel reaction involves the condensation of benzaldehydes with activated

methylene compounds in the presence of piperidine and is used to overcome the inherent

difficulties associated with the synthesis of coumarins via the Perkin reaction. Various

coumarins have been prepared via Knoevenagel condensation of salicylaldehyde with

activated methylene compounds as illustrated in (Scheme 4) 98

.

Introduction

Scheme 4: Knoevengel synthesis of 3-substituted coumarins

Two different mechanisms have been proposed for Knoevenagel reaction 99

. In the first

(Scheme 5a) formation of an imine or iminium salt (45) with the piperidine is followed by

reaction with the enolate of the active methylene compound elimination of the piperidine

and intramolecular ring closure to give the coumarin (46). The second proposal

(Scheme 5b) involves attack by the carbanion produced by deprotonation of the active

methylene compound by the amine on the carbonyl group to give intermediate (47). Proton

transfer, ring-closure via acyl substitution and dehydration then gives the coumarin (46).

Scheme 5: Mechanism of Knoevengel reaction

Bogdal et al 100

has shown that under microwave irradiation the Knoevenagel

condensation under solvent free conditions can be successfully applied to the synthesis of a

number of coumarins with yields up of 94% (Scheme 6).

Introduction

Scheme 6: Synthesis of 3,7,8 substituted coumarins by microwave irradiation

3.2) Wittig reaction:

Mali and Yadav 101,102

developed a preparation of coumarins via Wittig olefination

cyclization of 3-(2-hydroxyaryl)propenoic esters (Scheme 7). Cyclization under olefination

conditions depends on formation of the Z-alkene intermediate (53) and concomitant

formation of the E-alkenes is often a problem. This difficulty may be addressed by heating

the reaction mixture or by photochemical isomerization but these methods suffer from

variable yields inconvenient work-up or both. In an attempt to solve these problems

McNab and co-workers 103,104

showed that the cyclization takes place in consistently high

yield when the isolated 3-(2-hydroxyaryl)propenoic esters (53) are subjected to flash

vacuum pyrolysis (FVP). While the E-configuration of the double bond precludes

cyclization barrier to isomerization is overcome by the high temperature.

Scheme 7: Wittig synthesis of 3,6 substituted coumarins

The synthesis of coumarins by condensing o-hydroxybenzaldehydes or o-hydroxy

acetophenones (55) with the stable phosphorane (ethoxycarbonylmethylene)-

triphenylphosphorane has also been reported (Scheme 8).105

Uriarte et al.106

have also made

use of the Wittig reaction in the synthesis of potential antipsychotic compounds containing

the coumarin moiety by subjecting keto diphenols to a Wittig reaction with

Introduction

(ethoxycarbonylmethylene)triphenylphosphorane to give the expected 7-ethoxycoumarin

in rather poor yield (24%) and 7-hydroxycoumarin in (70%).

Scheme 8: Wittig synthesis of 4-substituted coumarins using stabilized phosphoranes

A new and efficient route to the synthesis of 4-carboxymethylcoumarins (61) (Scheme 9)

based on an aromatic electrophilic substitution reaction between the conjugate base of a

substituted phenol and the betaine formed by the addition of triphenylphospine to dimethyl

acetylenedicarboxylate (DMAD) has also been reported.107

This method complements

older established methods and offers significant advantages for the synthesis of coumarins

having acid-sensitive functional groups.

Scheme 9: Wittig synthesis of 6-substituted-coumarin-4-carboxylates

3.3) Perkin reaction:

Perkin reaction 108

involves heating an o-hydroxybenzaldehyde with acetic anhydride in

the presence of sodium acetate at a high temperature (ca. 200 oC) to afford a

trans-cinnamic acid. Optimum yields of coumarins are obtained when a 1:2 molar ratio of

aldehyde to anhydride is used. Isomerization of the trans-cinnamic acid by irradiation or

treatment with iodine followed by cyclization affords the coumarin (63) (Scheme 10).109

The disadvantage of this approach is the generally poor yield of the coumarin obtained

due to the production of tarry materials under the severe reaction conditions of the Perkin

synthesis.

Introduction

Scheme 10: Perkin synthesis of 7-hydroxy-6-methoxy-coumarin

Coumarin is also formed in the reaction of acetic anhydride and salicylaldehyde in the

presence of trimethylamine as the base catalyst (Scheme 11).110

Scheme 11: Perkin synthesis of coumarin

3.4) Pechmann reaction:

Pechmann reaction is a widely used method for preparing coumarins in good yield it

involves reacting a phenol with a β-oxo ester in the presence of a catalyst. The Pechmann

reaction has been carried out using both homogeneous acid catalysts [such as

sulphuric,111a,b

hydrochloric, phosphoric and trifluoroacetic acids,112

and with Lewis acids

such as zinc chloride,113

iron(III) chloride, tin(IV) chloride, titanium chloride and

aluminium chloride114a

] and heterogeneous catalysts [such as cationexchange resins,

Nafion-H, zeolite-HBEA and other solid acids].114b

Recently, microwave irradiation has

also been applied to accelerate this reaction.114c

Zhan-Hui Zhang et al.115

reported the

synthesis of coumarins via the Pechmann reaction catalysed by montmorilonite K-10 or

KSF in yields of up to 96% (Scheme 12). This procedure is environmentally friendly and

inexpensive compared to previous methods.

Introduction

Scheme 12: Pechmann synthesis of substituted 4-methyl-coumarins

The use of the cation exchange resins Zeokarb 225 and Amberlite IR 120 as condensing

agents in the synthesis of hydroxycoumarins has also been reported.116a

The main

advantages of cation exchange resins are that they simplify the isolation of the product and

tend to be relatively inexpensive. In order to obtain a maximum yield of the coumarin

between 20 and 40% of the resin by weight of the total reactants is used. The reaction is

considered to involve the following steps :- (i) addition across the double bond of the

enolic form of the β-keto ester (ii) ring closure and (iii) dehydration (Scheme 13).116b

Scheme 13: Mechanism of Pechmann reaction

Bekkum et al.117

have reported the synthesis of 7-hydroxycoumarin in 81% yield using a

solid-acid catalysed reaction of phenols with carboxylic acids (or their esters). Resorcinol

(69) and acrylic acid (73) in the presence of zeolite H-beta [Si/Al =14] or Amberlyst-15

undergo esterification followed by ring closure (Scheme 14) to give both 7-hydroxy-3,4-

dihydrocoumarin (75) (66%) and 3,4,6,7-tetrahydrobenzo[1,2-b:5,4-b]dipyran-2,8-dione

(76). Another approach involves the reaction of resorcinol and propynoic acid (77) in the

Introduction

presence of zeolite H-beta catalyst at high temperature (150 oC) (Scheme 15). In a third

approach ethyl acetoacetate was reacted with resorcinol (Scheme 16) (Pechmann reaction)

to afford 7-hydroxy-4-methylcoumarin (72).

Scheme 14: Synthesis of 3,4,6,7- tetrahydrobenzo[1,2-b:5,4-b]dipyran-2,8-dione

Scheme 15: Synthesis of 7-hydroxy coumarin

Scheme 16: Synthesis of 7-hydroxy-4-methyl coumarin

Kad et al.118

have reported the use of a microwave–assisted Pechmann reaction in the rapid

and simple preparation of substituted coumarins in yields of 72-82%, from substituted

phenols and methyl acetoacetate in the presence of H2SO4 (Scheme 17).

Introduction

Scheme 17: Synthesis of 7-hydroxy-4-methyl coumarin by microwave irradiation

4) Spectral characteristics of hydroxy coumarins:

Coumarins and their derivatives exhibit characteristic IR, UV, 1H NMR,

13C NMR and

mass spectral data which are extremely useful in monitoring the course of reactions as well

as identification of the products of the synthesis. Some salient features of the spectral

characteristics of hydroxy coumarins are summarized here.

4.1) IR spectra:

Coumarin (72) and 4,6,7 substituted and 7, 8 heterocyclic ring fused coumarins show the

C=O absorption at 1700-1750 cm–1

.

4.2) UV spectra:

The UV spectrum of 7-hydroxy-4-methyl coumarin (72) and 4,6,7 substituted and 7, 8

heterocyclic ring fused coumarins shows absorption maxima at 270 and 311 nm arising

due to cinnamoyl chromophore. These absorption maxima are shifted to longer

wavelength when the fused heterocycle is in conjugation with the coumarin chromophore.

In general, all the coumarins exhibit blue to yellow fluoroscence on exposure to longer

wavelength UV radiation.

4.3) 1H NMR spectra:

In the 1H NMR spectrum of 7-hydroxy 4-methyl coumarin (72) the characteristic H-3

appears at δ 6.31 (s), methyl protons appeared at 2.49 (s), aromatic protons appeared at

6.92 (d, H-6, J=9.0 Hz), 6.94 (s, H-8), 7.57 (d, H-5, J=9.0 Hz).

Introduction

4.4) 13

C NMR spectra:

In the 13

C NMR spectrum of 7-hydroxy-4-methyl-coumarin (72) the coumarin carbonyl

appeared at 160.8 (2-C=O) and other carbon signal assignments are 157.1 (C-7), 154.7

(C-8a), 152.7 (C-4), 126.2 (C-5), 112.6 (C-6), 112.5 (C-3), 112.2 (C-4a), 102.1 (C-8), 19.4

(4-CH3).

Introduction

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Introduction

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